We compared the gene expression profile of two human prostate cancer cell lines, PC-3 and a more metastatic derivative of PC-3 called PC-3M. We discovered that the MxA gene was expressed as mRNA and protein in PC-3 but not in its more metastatic daughter line, PC-3M. We upregulated MxA expression in PC-3M cells and in LOX, a highly metastatic human melanoma cell line, and found that their motility and invasion were drastically curtailed in vitro and the metastatic ability of PC-3M was significantly reduced in xenografts in immunocompromisd mice. A screen with a panel of drugs showed that MxA expression in PC-3M could be increased by several small molecules, and this was accompanied by a decrease in cell motility. Further refinements of this line of inquiry might result in a new strategy for development of antimetastasis therapeutics. Approximately 50% of human prostate cancers exhibit a fusion of two genes on chromosome 21, TMPRS2 and ERG. This fusion is commonly associated with an invasive phenotype, and the gene fusion results in an interstitial deletion of that portion of chromosome 21 that encodes the MxA family genes, Mx1 and Mx2. We postulate that the loss of expression of Mx1/2 is responsible for the increased aggrssiveness of tumors with this genotype.